Tocilizumab

Class: Disease-modifying Antirheumatic Agents
Chemical Name: Immunoglobulin G1, anti-(human interleukin 6 receptor) (human-mouse monoclonal MRA heavy chain), disulfide with human-mouse monoclonal MRA k-chain, dimer
Molecular Formula: C₆₄₂₈H₉₉₇₆N₁₇₂₀O₂₀₁₈S₄₂
CAS Number: 375823-41-9
Brands: Actemra

• Serious Infections


• 
  

  Serious, sometimes fatal infections including tuberculosis (pulmonary or extrapulmonary disease), bacterial and viral infections, invasive fungal infections (may be disseminated), and other opportunistic infections reported.¹ (See Infectious Complications under Cautions.)

  
  


• 
  

  Carefully consider risks and benefits prior to initiating tocilizumab therapy in patients with chronic or recurring infections.¹

  
  


• 
  

  Evaluate patients for latent tuberculosis infection prior to and periodically during tocilizumab therapy; if indicated, initiate appropriate antimycobacterial regimen prior to initiating tocilizumab therapy.¹

  
  


• 
  

  Closely monitor patients for infection, including active tuberculosis in those with a negative tuberculin skin test, during and after treatment.¹ If serious infection develops, discontinue tocilizumab until infection is controlled.¹

  
  

REMS:

FDA approved a REMS for tocilizumab to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of tocilizumab and consists of the following: communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Biologic response modifier and a disease-modifying antirheumatic drug (DMARD); a recombinant humanized IgG₁ monoclonal antibody specific for interleukin-6 (IL-6) receptor.^{1 3 4 5 6 9 10 11 13}

Uses for Tocilizumab

Rheumatoid Arthritis in Adults

Used to manage moderately to severely active rheumatoid arthritis in adults who have had an inadequate response to one or more tumor necrosis factor (TNF; TNF-α) blocking agents.¹

Can be used alone or in combination with methotrexate or other nonbiologic DMARDs (e.g., hydroxychloroquine, leflunomide, minocycline, sulfasalazine⁷ ).^{1 3 4 5 6}

Do not use concomitantly with other biologic DMARDs, such as TNF blocking agents (e.g., adalimumab, certolizumab, etanercept, golimumab, infliximab), interleukin-1 (IL-1) receptor antagonists (e.g., anakinra), anti-CD20 monoclonal antibodies (e.g., rituximab), and selective costimulation modulators (e.g., abatacept); concomitant use has not been studied and there is a possibility of increased immunosuppression and increased risk of infection.¹

Tocilizumab Dosage and Administration

General

• 
  

  Do not initiate tocilizumab therapy in patients with ANC <2000/mm³, platelet count <100,000/mm³, or ALT or AST concentration >1.5 times the ULN.¹

  
  

Concomitant Therapy

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  Methotrexate, other nonbiologic DMARDs, NSAIAs, and corticosteroids may be continued in patients with rheumatoid arthritis.¹

  
  


• 
  

  Do not use concomitantly with other biologic DMARDs.¹ (See Rheumatoid Arthritis in Adults under Uses.)

  
  

REMS Program

• 
  

  FDA has approved a Risk Evaluation and Mitigation Strategy (REMS) for tocilizumab.¹⁴

  
  


• 
  

  The REMS program consists of a medication guide that must be provided to patients (see Advice to Patients) and a communication plan that includes initial and/or periodic communications targeting selected groups of clinicians.¹⁴

  
  


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  The goals are to inform patients and health care providers about the serious risks associated with the drug (see Cautions: Warnings/Precautions).¹⁴

  
  

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion once every 4 weeks.¹

Tocilizumab injection concentrate must be diluted prior to IV administration.¹

Allow tocilizumab infusion solutions to reach room temperature prior to administration.¹ (See Storage under Stability.)

Do not infuse tocilizumab simultaneously through the same IV line with other drugs.¹

Dilution

Dilute tocilizumab injection concentrate in 0.9% sodium chloride injection to provide a total volume of 100 mL (i.e., remove a volume of diluent equal to the total required volume of the injection concentrate from a 100-mL bag or bottle of 0.9% sodium chloride injection prior to adding the injection concentrate).¹ Slowly add the total required volume of tocilizumab injection concentrate to the diluent; gently invert bag or bottle to mix the solution.¹

Tocilizumab infusion solutions are compatible with polypropylene, polyethylene, and polyvinyl chloride infusion bags and polypropylene, polyethylene, and glass infusion bottles.¹

Discard any unused portion remaining in the vial since the injection concentrate contains no preservative.¹

Rate of Administration

Infuse dose over 60 minutes; do not administer by rapid IV injection (e.g., IV push or bolus).¹

Dosage

Adults

Rheumatoid Arthritis

IV

Initially, 4 mg/kg once every 4 weeks; may increase to 8 mg/kg once every 4 weeks based on clinical response.¹ Doses >800 mg are not recommended (see Special Populations under Pharmacokinetics).¹

Dosage Modification or Discontinuance for Toxicity

IV

If a serious infection, an opportunistic infection, or sepsis develops, discontinue tocilizumab until the infection is controlled.¹

If certain dose-related laboratory changes (i.e., elevated ALT or AST concentrations, neutropenia, thrombocytopenia) occur in patients receiving tocilizumab 8 mg/kg every 4 weeks, reduce tocilizumab dosage to 4 mg/kg every 4 weeks or temporarily interrupt or discontinue therapy (see tables).¹

Table 1. Recommended Dosage Adjustment Based on Changes in Liver Enzyme Laboratory Value

ALT or AST Value	Recommendation
>1 to 3 times ULN	Modify dosage of concomitant DMARDs if appropriate1
	For persistent increases within this range, reduce tocilizumab dosage to 4 mg/kg every 4 weeks or interrupt tocilizumab therapy until ALT/AST values have returned to normal1
>3 to 5 times ULN (confirmed by repeat testing)	Interrupt tocilizumab therapy until ALT/AST values are <3 times ULN and follow recommendations for ALT/AST values of >1 to 3 times ULN1
	For persistent increases of >3 times ULN, discontinue tocilizumab1
>5 times ULN	Discontinue tocilizumab1

Table 2. Recommended Dosage Adjustment Based on Absolute Neutrophil Count (ANC)

ANC (cells/mm3 )	Recommendation
>1000	Maintain current dosage1
500–1000	Interrupt tocilizumab therapy1
	When ANC is >1000/mm3, resume tocilizumab at 4 mg/kg every 4 weeks and increase to 8 mg/kg every 4 weeks as clinically indicated1
<500	Discontinue tocilizumab1

Table 3. Recommended Dosage Adjustment Based on Platelet Count

Platelet Count (cells/mm3)	Recommendation
50,0000–100,000	Interrupt tocilizumab therapy1
	When platelet count is >100,000/mm3, resume tocilizumab at 4 mg/kg every 4 weeks and increase to 8 mg/kg every 4 weeks as clinically indicated1
<50,000	Discontinue tocilizumab1

Prescribing Limits

Adults

Rheumatoid Arthritis

IV

Maximum 800 mg per dose.¹

Special Populations

Hepatic Impairment

Use is not recommended.¹

Renal Impairment

Dosage adjustment not necessary in patients with mild renal impairment; not evaluated in moderate or severe renal impairment.¹

Geriatric Patients

Manufacturer makes no specific dosage recommendations.¹

Cautions for Tocilizumab

Contraindications

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  Manufacturer states none known.¹

  
  

Warnings/Precautions

Warnings

Infectious Complications

Serious, sometimes fatal infections (including bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic infections) reported, particularly in patients receiving concomitant therapy with other immunosuppressive agents (e.g., methotrexate, corticosteroids).¹ Opportunistic infections include tuberculosis, cryptococcal infection, aspergillosis, candidiasis, and pneumocystosis.¹ Infections may be disseminated.¹

Do not initiate tocilizumab in patients with active infections, including localized infections.¹ Consider potential risks and benefits of the drug prior to initiating therapy in patients with a history of chronic, recurring, serious, or opportunistic infections; patients with underlying conditions that may predispose them to infections; and patients who have been exposed to tuberculosis or who have resided or traveled in regions where tuberculosis or mycoses are endemic.¹

Closely monitor patients during and after treatment with tocilizumab for the development of signs or symptoms of infection.¹ If new infection occurs during therapy, perform thorough diagnostic evaluation (appropriate for immunocompromised patient), initiate appropriate anti-infective therapy, and closely monitor patient.¹ If serious infection, opportunistic infection, or sepsis develops, discontinue tocilizumab until the infection is controlled.¹

Evaluate all patients for latent tuberculosis and for risk factors for tuberculosis prior to and periodically during therapy.¹ When indicated, initiate an appropriate antimycobacterial regimen for the treatment of latent tuberculosis infection prior to tocilizumab therapy.¹ Consider initiation of antimycobacterial therapy prior to initiation of tocilizumab in individuals with a history of latent or active tuberculosis in whom an adequate course of antimycobacterial treatment cannot be confirmed and in individuals with a negative test for latent tuberculosis who have risk factors for tuberculosis.¹ Consultation with a tuberculosis specialist is recommended when deciding whether to initiate antimycobacterial therapy.¹

Monitor all patients, including those with a negative test for latent tuberculosis, for active tuberculosis.¹

Viral reactivation can occur in patients receiving immunosuppressive therapies.¹ Herpes zoster exacerbation reported in patients receiving tocilizumab.¹

GI Perforation

GI perforation reported, usually as a complication of diverticulitis and most commonly in patients receiving concomitant therapy with NSAIAs, corticosteroids, or methotrexate.¹ The relative contribution of these agents versus tocilizumab to the occurrence of GI perforation remains to be determined.¹

Caution is advised if tocilizumab is used in patients at risk for GI perforation.¹

Promptly evaluate patients with new-onset abdominal symptoms for evidence of GI perforation.¹

Hematologic Effects

Possible neutropenia or thrombocytopenia.¹

Reduction in neutrophil count to <1000/mm³ reported in 1.8 or 3.4% of patients receiving tocilizumab 4 or 8 mg/kg every 4 weeks, respectively, in conjunction with nonbiologic DMARD therapy for 24 weeks; approximately one-half of cases occurred during first 8 weeks of therapy.¹ Decreases in neutrophil count to <1000/mm³ did not appear to be associated with serious infection.¹

Monitor neutrophil and platelet counts every 4–8 weeks in patients receiving tocilizumab.¹ Dosage adjustment or discontinuance may be necessary.¹ (See Dosage Modification or Discontinuance for Toxicity under Dosage and Administration.)

Hepatic Effects

Elevated transaminase concentrations may occur.¹ In clinical trials, changes were reversible following reduction of the tocilizumab or concomitant DMARD dosage or interruption of tocilizumab therapy and were not associated with clinical evidence of hepatic injury.¹

Incidence and magnitude of transaminase elevations were increased with concomitant use of hepatotoxic drugs (e.g., methotrexate).¹

Monitor serum ALT and AST every 4–8 weeks in patients receiving tocilizumab.¹ Monitor other liver function tests when clinically indicated.¹ Dosage adjustment or discontinuance of tocilizumab or concomitantly administered DMARDs may be necessary.¹ (See Dosage Modification or Discontinuance for Toxicity under Dosage and Administration.)

Effects on Serum Lipids

Increased serum concentrations of total cholesterol, triglycerides, LDL-cholesterol, and/or HDL-cholesterol reported.¹

Monitor lipoprotein concentrations 4–8 weeks after initiation of tocilizumab therapy and approximately every 24 weeks thereafter.¹ Manage lipid disorders as clinically appropriate.¹

Malignancies

Immunosuppressive therapy may increase the risk of malignancies.¹ Whether treatment with tocilizumab affects development of malignancies remains to be determined.¹ Malignancies were reported in clinical trials.¹

Sensitivity Reactions

Serious hypersensitivity reactions, including fatal anaphylaxis, reported;^{1 15} anaphylactic and anaphylactoid reactions generally have occurred during the second to fourth infusions of the drug.¹

Have appropriate agents and equipment available for immediate use in case a serious hypersensitivity reaction occurs.¹ If a serious hypersensitivity reaction occurs, immediately stop the drug infusion, provide appropriate supportive care, and permanently discontinue the drug.¹⁵

Nervous System Effects

Effect of tocilizumab on demyelinating disorders remains to be determined.¹ Multiple sclerosis and chronic inflammatory demyelinating polyneuropathy reported rarely in patients receiving tocilizumab.¹

Monitor patients receiving tocilizumab for signs and symptoms suggestive of a demyelinating disorder.¹ Exercise caution when considering tocilizumab therapy in patients with preexisting or recent-onset demyelinating disorders.¹

Immunization

Do not administer live vaccines to patients receiving tocilizumab.¹ Administer all age-appropriate vaccines, except for live vaccines, prior to initiation of tocilizumab therapy.¹

Information not available regarding immune response to vaccines in patients receiving tocilizumab or regarding secondary transmission of infection from individuals receiving live vaccines to patients receiving tocilizumab.¹

Laboratory Monitoring

Monitor neutrophil counts, platelet counts, and serum ALT and AST concentrations every 4–8 weeks during tocilizumab therapy.¹ Monitor other liver function tests when clinically indicated.¹ Monitor lipoprotein concentrations 4–8 weeks after initiation of therapy and approximately every 24 weeks thereafter.¹

Immunogenicity

Antibodies to tocilizumab detected in sera of about 2% of tocilizumab-treated patients; about 11% of these patients experienced hypersensitivity reactions resulting in drug discontinuance.¹ Neutralizing antibodies detected in about 1% of patients receiving the drug.¹

Specific Populations

Pregnancy

Category C.¹

Pregnancy registry at 877-311-8972.¹

Lactation

Not known whether tocilizumab is distributed into milk or is absorbed systemically following ingestion.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established in children.¹

Geriatric Use

Geriatric patients in general may have a higher incidence of infections than younger adults.¹ In clinical trials of tocilizumab, serious infections reported more frequently in patients ≥65 years of age than in younger adults.¹ Use tocilizumab with caution in this age group.¹

Hepatic Impairment

Safety and efficacy not established in patients with hepatic impairment, including those with serologic evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.¹ Use in patients with active hepatic disease or hepatic impairment is not recommended.¹

Renal Impairment

Not evaluated in patients with moderate to severe renal impairment.¹

Common Adverse Effects

Upper respiratory tract infection,^{1 3 4 5} nasopharyngitis,^{1 3 4} headache,^{1 3 4 5} hypertension,^{1 3 4 5} increased ALT concentrations.^{1 3 4 5}

Interactions for Tocilizumab

May alter expression of CYP isoenzymes including 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4; effects on CYP2C8 or transporters (e.g., P-glycoprotein) not elucidated.¹

Drugs Metabolized by Hepatic Microsomal Enzymes

Possible increased metabolism of drugs metabolized by CYP isoenzymes.¹ Because IL-6 may down-regulate CYP isoenzymes, inhibition of IL-6 by tocilizumab in rheumatoid arthritis patients may restore CYP enzyme activity to higher levels.¹ Effects on CYP enzyme activity may persist for several weeks after drug discontinuance.¹

Drugs metabolized by CYP isoenzymes that have a low therapeutic index and require individualized dosing: Carefully monitor therapeutic effect and serum concentrations following initiation or discontinuance of tocilizumab; adjust dosage as needed.¹

Other CYP3A4 substrates: Caution advised when a reduction in efficacy would be undesirable.¹

Specific Drugs

Drug	Interaction	Comments
Contraceptives, oral	Possible increased metabolism of oral contraceptive1	Caution advised1
Corticosteroids	Concomitant use does not appear to affect clearance of tocilizumab1
Cyclosporine	Possible increased metabolism of cyclosporine1	Carefully monitor therapeutic effect and serum concentrations of cyclosporine following initiation or discontinuance of tocilizumab; adjust dosage as needed1
Dextromethorphan	Reduction in exposure to dextromethorphan and dextrorphan following initiation of tocilizumab reported in rheumatoid arthritis patients receiving dextromethorphan1 (In rheumatoid arthritis patients not receiving tocilizumab, systemic exposure to dextromethorphan is similar to, but exposure to dextrorphan is decreased, compared with values in healthy individuals1 )
DMARDs, biologic (e.g., TNF blocking agents)	Possible increased immunosuppression and increased risk of infection; concomitant use not studied1	Concomitant use not recommended1
HMG CoA reductase inhibitors (statins)	Statins metabolized by CYP isoenzymes (e.g., atorvastatin, lovastatin): Possible increased metabolism of the statin1 Simvastatin: Reduction in exposure to simvastatin and simvastatin acid following initiation of tocilizumab reported in rheumatoid arthritis patients receiving simvastatin (values were similar to or slightly higher than values observed after simvastatin administration in healthy individuals); exposure to simvastatin and simvastatin acid increased following discontinuance of tocilizumab1 (Systemic exposure to simvastatin and simvastatin acid is increased in rheumatoid arthritis patients not receiving tocilizumab compared with healthy individuals)1	Caution advised1 When selecting simvastatin dosages for patients with rheumatoid arthritis, consider the potential for altered systemic exposure to the drug following initiation or discontinuance of tocilizumab1
Methotrexate	Concomitant use does not appear to affect clearance of tocilizumab or exposure to methotrexate1
NSAIAs	Concomitant use does not appear to affect clearance of tocilizumab1
Omeprazole	Reduction in exposure to omeprazole following initiation of tocilizumab reported in rheumatoid arthritis patients receiving omeprazole (values were slightly higher than values observed after omeprazole administration in healthy individuals)1 (Systemic exposure to omeprazole is increased in rheumatoid arthritis patients not receiving tocilizumab compared with healthy individuals1 )
Theophylline	Possible increased metabolism of theophylline1	Carefully monitor therapeutic effect and serum concentrations of theophylline following initiation or discontinuance of tocilizumab; adjust dosage as needed1
Vaccines, live		Avoid live vaccines (see Immunization under Cautions)1
Warfarin	Possible increased metabolism of warfarin1	Carefully monitor therapeutic effect of warfarin following initiation or discontinuance of tocilizumab; adjust dosage as needed1

Tocilizumab Pharmacokinetics

Absorption

Plasma Concentrations

Increase in dosage from 4 mg/kg to 8 mg/kg every 4 weeks associated with greater-than-proportional increases in AUC and trough plasma concentrations.¹

Distribution

Extent

Not known whether tocilizumab is distributed into milk.¹

Elimination

Half-life

Steady-state half-life: Up to 11 days at dosage of 4 mg/kg every 4 weeks; up to 13 days at dosage of 8 mg/kg every 4 weeks.¹

Clearance decreases as dose increases.¹ At low tocilizumab concentrations, concentration-dependent nonlinear clearance plays a major role in determining total drug clearance; at higher concentrations, nonlinear pathway is saturated and clearance is determined mainly by linear clearance.¹

Special Populations

As body size increases, linear clearance increases.¹ Following a weight-based dose of 8 mg/kg, systemic drug exposure is substantially greater in individuals weighing >100 kg than in those weighing <60 kg.¹

Pharmacokinetics not formally studied in renal or hepatic impairment.¹ Population pharmacokinetic data indicate that mild renal impairment (Cl_cr ≥50 mL/minute but <80 mL/minute) does not alter pharmacokinetics.¹

Stability

Storage

Parenteral

Injection Concentrate

2–8°C; do not freeze.¹ Protect vials from light.¹

Following dilution, 2–8°C or room temperature for up to 24 hours.¹ Protect from light.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible
Sodium chloride 0.9%

Actions

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  Binds specifically to both soluble and membrane-bound IL-6 receptors and inhibits IL-6-mediated signaling through these receptors, thereby resulting in a reduction in inflammatory mediator production.^{1 3 4 5 9 10}

  
  


• 
  

  IL-6, a pleiotropic proinflammatory cytokine, is produced by various cell types (e.g., T-cells, B-lymphocytes, monocytes, fibroblasts, synoviocytes, endothelial cells) and has a broad spectrum of biologic activities,^{1 3 4 5 9 10 12} including involvement in T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, stimulation of hematopoietic precursor cell proliferation and differentiation, and induction of osteoclast differentiation and activation.^{1 4 5 9 10 12}

  
  


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  IL-6 is overexpressed in synovial tissue in patients with rheumatoid arthritis and is thought to contribute to synovial proliferation and joint destruction in patients with the disease.^{4 9 10 12} Elevated levels of IL-6 in serum and synovial fluid correlate with clinical and laboratory measures of disease activity in patients with rheumatoid arthritis.^{3 5 9 10 12}

  
  

Advice to Patients

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  A copy of the manufacturer’s patient information (medication guide) for tocilizumab must be provided to all patients.¹ (See REMS Program under Dosage and Administration.) Importance of advising patients about potential benefits and risks of tocilizumab.¹ Importance of patients reading the medication guide prior to initiation of therapy and each time they receive an infusion of the drug.¹

  
  


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  Risk of increased susceptibility to infection.¹ Importance of informing clinicians immediately if any signs or symptoms suggestive of infection (e.g., fever; sweating; cough; dyspnea; diarrhea; burning or pain upon urination; warm, red, or painful skin) develop.¹

  
  


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  Risk of GI perforation.¹ Importance of informing clinician immediately if severe, persistent abdominal pain occurs.¹

  
  


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  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., biologic antirheumatic drugs, immunizations) and OTC drugs, as well as any other illnesses (e.g., history of tuberculosis; concomitant, chronic, or recurring infections).¹

  
  


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  Importance of periodic laboratory monitoring.¹

  
  


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  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


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  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Tocilizumab (recombinant)

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection concentrate, for IV infusion	20 mg/mL	Actemra	Genentech

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Genentech. Actemra (tocilizumab) injection prescribing information. South San Francisco, CA; 2011 Jan.

2. Felson DT, Anderson JJ, Boers M et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995; 38:727-35. [PubMed 7779114]

3. Jones G, Sebba A, Gu J et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010; 69:88-96. [PubMed 19297346]

4. Smolen JS, Beaulieu A, Rubbert-Roth A et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008; 371:987-97. [PubMed 18358926]

5. Genovese MC, McKay JD, Nasonov EL et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008; 58:2968-80. [PubMed 18821691]

6. Emery P, Keystone E, Tony HP et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008; 67:1516-23. [PubMed 18625622]

7. Saag KG, Teng GG, Patkar NM et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008; 59:762-84. [PubMed 18512708]

8. Hoffmann-LaRoche Inc. FDA arthritis advisory committee briefing document for tocilizumab biologic license application 125276. Nutley, NJ; 2008 Jul 29.

9. Plushner SL. Tocilizumab: an interleukin-6 receptor inhibitor for the treatment of rheumatoid arthritis. Ann Pharmacother. 2008; 42:1660-8. [PubMed 18957621]

10. Sebba A. Tocilizumab: the first interleukin-6-receptor inhibitor. Am J Health Syst Pharm. 2008; 65:1413-8. [PubMed 18653811]

11. . Drugs for rheumatoid arthritis. Treat Guidel Med Lett. 2009; 7:37-46; quiz 47-8. [PubMed 19390497]

12. Park JY, Pillinger MH. Interleukin-6 in the pathogenesis of rheumatoid arthritis. Bull NYU Hosp Jt Dis. 2007; 65 Suppl 1:S4-10. [PubMed 17708744]

13. Marti L, Golmia R, Golmia AP et al. Alterations in cytokine profile and dendritic cells subsets in peripheral blood of rheumatoid arthritis patients before and after biologic therapy. Ann N Y Acad Sci. 2009; 1173:334-42. [PubMed 19758170]

14. Actemra (tocilizumab) risk evaluation and mitigation strategy (REMS). From FDA website. Accessed 2010 Mar 18.

15. Barron H. Dear healthcare professional letter regarding important safety information regarding tocilizumab (Actemra/Roactemra). South San Francisco, CA; 2010 Sep.

16. Felson DT, Anderson JJ, Boers M et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995; 38:727-35. [PubMed 7779114]

17. Felson DT, Anderson JJ, Boers M et al. The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum. 1993; 36:729-40. [PubMed 8507213]

18. Felson DT, Anderson JJ, Lange MLM et al. Should improvement in rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in core set measures, rather than twenty percent. Arthritis Rheum. 1998; 41:1564-70. [IDIS 411264] [PubMed 9751088]

More Tocilizumab resources

• Tocilizumab Side Effects (in more detail)
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• Tocilizumab Drug Interactions
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• 0 Reviews for Tocilizumab - Add your own review/rating

• Tocilizumab MedFacts Consumer Leaflet (Wolters Kluwer)


• Tocilizumab Professional Patient Advice (Wolters Kluwer)


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• Actemra Prescribing Information (FDA)


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Thyrogen

thyrotropin alfa

Dosage Form: injection, powder, for solution

Thyrogen Description

Thyrogen® (thyrotropin alfa for injection) contains a highly purified recombinant form of human thyroid stimulating hormone (TSH), a glycoprotein which is produced by recombinant DNA technology. Thyrotropin alfa is synthesized in a genetically modified Chinese hamster ovary cell line.

Thyrotropin alfa is a heterodimeric glycoprotein comprised of two non-covalently linked subunits, an alpha subunit of 92 amino acid residues containing two N-linked glycosylation sites and a beta subunit of 118 residues containing one N-linked glycosylation site. The amino acid sequence of thyrotropin alfa is identical to that of human pituitary thyroid stimulating hormone.

Both thyrotropin alfa and naturally occurring human pituitary thyroid stimulating hormone are synthesized as a mixture of glycosylation variants. Unlike pituitary TSH, which is secreted as a mixture of sialylated and sulfated forms, thyrotropin alfa is sialylated but not sulfated. The biological activity of thyrotropin alfa is determined by a cell-based bioassay. In this assay, cells expressing a functional TSH receptor and a cAMP-responsive element coupled to a heterologous reporter gene, luciferase, enable the measurement of rhTSH activity by measuring the luciferase response. The specific activity of thyrotropin alfa is determined relative to an internal Genzyme reference standard that was calibrated against the World Health Organization (WHO) human TSH reference standard.

Thyrogen is supplied as a sterile, non-pyrogenic, white to off-white lyophilized product, intended for intramuscular (IM) administration after reconstitution with Sterile Water for Injection, USP. Each vial of Thyrogen contains 1.1 mg thyrotropin alfa, 36 mg Mannitol, 5.1 mg Sodium Phosphate, and 2.4 mg Sodium Chloride.

After reconstitution with 1.2 mL of Sterile Water for Injection, USP, the thyrotropin alfa concentration is 0.9 mg/mL. The pH of the reconstituted solution is approximately 7.0.

Thyrogen - Clinical Pharmacology

Pharmacodynamics

Thyrotropin alfa (recombinant human thyroid stimulating hormone) is a heterodimeric glycoprotein produced by recombinant DNA technology. It has comparable biochemical properties to the human pituitary TSH. Binding of thyrotropin alfa to TSH receptors on normal thyroid epithelial cells or on well-differentiated thyroid cancer tissue stimulates iodine uptake and organification, and synthesis and secretion of thyroglobulin (Tg), triiodothyronine (T3) and thyroxine (T4).

In patients with thyroid cancer, a near-total or total thyroidectomy is usually performed. Thyroidectomy is usually followed by radioiodine treatment to remove any remnant of normal thyroid tissue and microscopic residues of malignant tissue. Prior to radioiodine remnant ablation, serum TSH elevation is necessary to promote uptake of radioiodine by thyroid cells or thyroid cancer cells. Elevation of TSH may be achieved by withholding of synthetic thyroid hormone medication after thyroidectomy, with subsequent rise of endogenous pituitary thyroid stimulating hormone; or by administration of thyrotropin in the setting of synthetic thyroid hormone administration. After remnant ablation, patients are placed on synthetic thyroid hormone supplements to replace endogenous hormone and to suppress serum levels of TSH in order to avoid TSH-stimulated tumor growth. Thereafter, patients are followed for the presence of remnants, or of residual or recurrent cancer, by thyroglobulin (Tg) testing, usually with radioiodine imaging. This follow-up testing is most effective when conducted under TSH stimulation, achieved either by thyroid hormone withdrawal or administration of thyrotropin. Thyroid hormone withdrawal results in hypothyroidism with subsequent elevation of endogenous pituitary TSH; when thyrotropin is used, patients remain on thyroid hormone suppressive therapy and are euthyroid.

Pharmacokinetics

The pharmacokinetics of Thyrogen were studied in 16 patients with well-differentiated thyroid cancer given a single 0.9 mg IM dose. Mean peak concentrations of 116 ± 38 mU/L were reached between 3 and 24 hours after injection (median of 10 hours). The mean apparent elimination half-life was 25 ± 10 hours. The organ(s) of TSH clearance in man have not been identified, but studies of pituitary-derived TSH suggest the involvement of the liver and kidneys.

Clinical Trials

Clinical Trials of Thyrogen as an Adjunctive Diagnostic Tool:

Two phase 3 clinical trials were conducted in 358 evaluable patients with well-differentiated thyroid cancer to compare 48-hour radioiodine (131I) whole body scans obtained after Thyrogen to whole body scans after thyroid hormone withdrawal. One of these trials also compared Tg levels obtained after Thyrogen to those on thyroid hormone suppressive therapy, and to those after thyroid hormone withdrawal. All Tg testing was performed in a central laboratory using a radioimmunoassay (RIA) with a functional sensitivity of 2.5 ng/mL. Only successfully ablated patients (defined as patients who have undergone total or near-total thyroidectomy with or without radioiodine ablation, and with < 1% uptake in the thyroid bed on a scan after thyroid hormone withdrawal) without detectable anti-thyroglobulin antibodies were included in the Tg data analysis. The maximum Thyrogen Tg value was obtained 72 hours after the final Thyrogen injection, and this value was used in the analysis (see DOSAGE AND ADMINISTRATION).

Diagnostic Radioiodine Whole Body Scan Results

Table 1 summarizes the scan data in patients with positive scans after withdrawal of thyroid hormone from the diagnostic phase 3 studies:

Table 1: Scan Data in Patients with Positive Scans

	# scan pairs by disease category	#(%) scan pairs in which Thyrogen® scan detected disease seen on withdrawal scan	#(%) scan pairs in which Thyrogen® scan did not detect disease seen on withdrawal scan
* Across all studies, uptake was detected on the Thyrogen scan but not observed on the scan after thyroid hormone withdrawal in 5 patients with remnant or cancer in the thyroid bed.
First Phase 3 Study (0.9 mg IM qd x 2)
positive for remnant or cancer in thyroid bed	48	39(81)	9(19)
metastatic disease	15	11(73)	4(27)
total positive withdrawal scans*	63	50(79)	13(21)
Second Phase 3 Study (0.9 mg IM qd x 2)
positive for remnant or cancer in thyroid bed	35	30(86)	5(14)
metastatic disease	9	6(67)	3(33)
total positive withdrawal scans*	44	36(82)	8(18)
Second Phase 3 Study (0.9 mg IM q 72 hrs x 3)
positive for remnant or cancer in thyroid bed	41	35(85)	6(15)
metastatic disease	14	12(86)	2(14)
total positive withdrawal scans*	55	47(85)	8(15)

Across the two clinical studies, the Thyrogen scan failed to detect remnant and/or cancer localized to the thyroid bed in 16% (20/124) of patients in whom it was detected by a scan after thyroid hormone withdrawal. In addition, the Thyrogen scan failed to detect metastatic disease in 24% (9/38) of patients in whom it was detected by a scan after thyroid hormone withdrawal.

Thyroglobulin (Tg) Results:

Thyrogen Tg Testing Alone and in Combination with Diagnostic Whole Body Scanning: Comparison with Results after Thyroid Hormone Withdrawal:

In Tg antibody negative patients with a thyroid remnant or cancer as defined by a withdrawal Tg ≥ 2.5 ng/mL or a positive scan (after thyroid hormone withdrawal or after radioiodine therapy), the Thyrogen Tg was ≥ 2.5 ng/mL in 69% (40/58) of patients after 2 doses of Thyrogen, and in 80% (53/66) of patients after 3 doses of Thyrogen.  Across both dosage groups, 45% had a Tg ≥ 2.5 ng/mL on thyroid hormone suppressive therapy.

In these same patients, adding the whole body scan increased the detection rate of thyroid remnant or cancer to 84% (49/58) of patients after 2 doses of Thyrogen and 94% (62/66) of patients after 3 doses of Thyrogen.

Thyrogen Tg Testing Alone and in Combination with Diagnostic Whole Body Scanning in Patients with Confirmed Metastatic Disease:

Metastatic disease was confirmed by a post-treatment scan or by lymph node biopsy in 35 patients. Thyrogen Tg was ≥ 2.5 ng/mL in all 35 patients while Tg on thyroid hormone suppressive therapy was ≥ 2.5 ng/mL in 79% of these patients.

In this same cohort of 35 patients with confirmed metastatic disease, the Thyrogen Tg levels were below 10 ng/mL in 27% (3/11) of patients after 2 doses of Thyrogen and in 13% (3/24) of patients after 3 doses of Thyrogen. The corresponding thyroid hormone withdrawal Tg levels in these 6 patients were 15.6 – 137 ng/mL. The Thyrogen scan detected metastatic disease in 1 of these 6 patients (see INDICATIONS AND USAGE, Considerations in the Use of Thyrogen).

As with thyroid hormone withdrawal, the intra-patient reproducibility of Thyrogen testing with regard to both Tg stimulation and radioiodine imaging has not been studied.

Clinical Trials of Thyrogen as an Adjunct to Radioiodine Therapy to Achieve Thyroid Remnant Ablation:
A randomized prospective clinical trial comparing the rates of thyroid remnant ablation achieved after preparation of patients either with hypothyroidism or Thyrogen has been performed. Patients (n = 63) with low-risk well-differentiated thyroid cancer underwent near-total thyroidectomy, then were equally randomized to the Hypothyroid group (serum TSH > 25 µU/mL) or thyroxine replacement (Euthyroid group; serum TSH < 5 µU/mL). Patients in the Euthyroid group then received Thyrogen 0.9 mg IM daily on two consecutive days, and then radioiodine 24 hours after the second dose of Thyrogen. All patients received 100 mCi 131I ± 10% with the intent to ablate any thyroid remnant tissue. The primary endpoint of the study, which was the success of ablation, was assessed 8 months later by a Thyrogen-stimulated radioiodine scan. Patients were considered successfully ablated if there was no visible thyroid bed uptake on the scan, or if visible, uptake was less than 0.1%. Table 2 summarizes the results of this evaluation.

Table 2: Results from the Remnant Ablation Clinical Trial

Group*	Mean Age (Yr)	Gender (F:M)	Cancer Type (Pap:Fol)	Ablation Criterion (Measure at 8 Months)
* 60 per protocol patients with interpretable scan data.  95% CI for difference in ablation rates, rTSH minus THW, = -6.9% to 27.1%. † Interpretation by 2 of 3 reviewers.  95% CI for difference in ablation rates, rTSH minus THW, = -30.5% to 9.1%. Abbreviations: fol = follicular, pap = papillary, THW = thyroid hormone withdrawal
				Thyroid Bed Activity ‹0.1%	No Visible Thyroid Bed Activity†
THW (N=28)	43	24:6	29:1	28/28 (100)	24/28 (86)
rTSH (N=32)	44	26:7	30:3	32/32 (100)	24/32 (75)

The mean radiation dose to blood was 0.266±0.061 mGy/MBq in the Euthyroid group and 0.395±0.135 mGy/MBq in the Hypothyroid group (p<0.0001). Radioiodine residence time in remnant tissue was 0.9±1.3 hours in the Euthyroid group and 1.4±1.5 hours in the Hypothyroid group. It is not known whether this difference in radiation exposure would convey a clinical benefit.

A follow-up study was conducted on patients who previously completed the initial study. The main objective of the follow-up study was to confirm the status of thyroid remnant ablation by using Thyrogen-stimulated radioiodine static neck imaging after a median follow-up of 3.7 years (range 3.4 to 4.4 years) following radioiodine ablation. Thyroglobulin testing was also performed.

Sixty-one male and female thyroidectomized patients who participated in the original study (Table 2) were planned for inclusion in this follow-up study. Fifty-one patients were enrolled in this study; 48 received Thyrogen for remnant neck/whole body imaging and/or Tg testing (three patients underwent the collection of medical history portion of the study but did not undergo stimulated neck/WB scanning or testing). Patients were still considered to be successfully ablated if there was no visible thyroid bed uptake on the scan, or if visible, uptake was less than 0.1% (Table 3).

Table 3: Summary of Thyroid Remnant Ablation During the 3.7-Year Follow-Up of Patients Treated in the Initial Study

Uptake in Thyroid Bed	Former THW* Group (n=18)  N (%)	Former rTSH Group (n=25)  N (%)
* THW = Thyroid Hormone Withdrawal
No Visibile Uptake in Thyroid Bed or Uptake ‹ 0.1%	18 (100)	25 (100)

Of note, 9 patients (distributed similarly in both treatment groups: 5 former Hypothyroid and 4 former Euthyroid patients) received 131I (approximately 100 mCi (3.7 GBq) or more) during the period between the end of the initial study and the initiation of this follow-up study. When considering only the patients who did not receive radioiodine during the period between studies, 100% of patients in both treatment subgroups (15 former Hypothyroid and 22 former Euthyroid patients) were successfully ablated according to the predefined study criteria.

Successful ablation also can be inferred when the Thyrogen-stimulated serum Tg level is < 2 ng/mL, although a lower Tg level might also be used as a criterion by some experts. The presence of antithyroglobulin antibodies can render results of thyroglobulin assays uninterpretable. A total of 17 patients in the former Hypothyroid group and 20 patients in the former Euthyroid group had antithyroglobulin antibody levels <5 units/mL. Of these patients, 16/17 (94%) of patients in the former Hypothyroid group and 19/20 (95%) of patients in the former Euthyroid group had stimulated serum thyroglobulin levels of <2 ng/mL.

No patient had a definitive cancer recurrence during the 3.7 years of follow-up. Overall, 48/51 patients (94%) had no evidence of cancer recurrence, 1 patient had possible cancer recurrence (although it was not clear whether this patient had a true recurrence or persistent tumor from the regional disease noted at the start of the initial study), and 2 patients could not be assessed.

In summary, in this study and its follow-up study, Thyrogen was noninferior to thyroid hormone withholding for elevation of TSH levels as adjunctive therapy to radioiodine for post-surgical ablation of remnant thyroid tissue.

Several publications describe studies or series of patients in which Thyrogen was used as an adjunct to radioiodine for the ablation of thyroid remnant tissue. Some publications1-4 found comparable rates of remnant ablation whether patients were prepared using hypothyroidism or Thyrogen, whereas another publication5 found that hypothyroidism had a better rate of success than Thyrogen, although in that study the radioiodine was administered 48 hours rather than 24 hours after the second dose of Thyrogen. Follow-up for 2.5 years of patients undergoing ablation at Memorial Sloan-Kettering has shown that use of Thyrogen results in a low rate of tumor recurrence that is comparable to the rate seen after use of withdrawal from thyroxine.6

Quality of Life:

Quality of Life (QOL) was measured during both the diagnostic study and the ablation of thyroid remnant study, using the SF-36 Health Survey, a standardized, patient-administered instrument assessing QOL across eight domains measuring both physical and mental functioning. In the diagnostic study and in the remnant ablation study, following Thyrogen administration, little change from baseline was observed in any of the eight QOL domains of the SF-36. Following thyroid hormone withdrawal in the diagnostic study, statistically significant negative changes were noted in all eight QOL domains of the SF-36. The difference between treatment groups was statistically significant (p<0.0001) for all eight QOL domains, favoring Thyrogen over thyroid hormone withdrawal (Figure 1). In the remnant ablation study, following thyroid hormone withdrawal, statistically significant negative changes were noted in five of the eight QOL domains (physical functioning, role physical, vitality, social functioning and mental health). The difference between treatment groups was statistically significant (p<0.05), favoring Thyrogen over thyroid hormone withdrawal.

FIGURE 1 – SF-36 HEALTH SURVEY RESULTS

QUALITY OF LIFE DOMAINS

DIAGNOSTIC INDICATION

Hypothyroid Signs and Symptoms - Diagnostic Indication:

Thyrogen administration was not associated with the signs and symptoms of hypothyroidism that accompanied thyroid hormone withdrawal as measured by the Billewicz scale. Statistically significant worsening in all signs and symptoms were observed during the hypothyroid phase (p<0.01) (Figure 2). 

FIGURE 2 - HYPOTHYROID SYMPTOM ASSESSMENT BILLEWICZ SCALE

DIAGNOSTIC INDICATION

0.9 mg Thyrogen® q 24 hours x 2 doses

Indications and Usage for Thyrogen

Thyrogen (thyrotropin alfa for injection) is indicated for use as an adjunctive diagnostic tool for serum thyroglobulin (Tg) testing with or without radioiodine imaging in the follow-up of patients with well-differentiated thyroid cancer.

Thyrogen (thyrotropin alfa for injection) is indicated for use as an adjunctive treatment for radioiodine ablation of thyroid tissue remnants in patients who have undergone a near-total or total thyroidectomy for well-differentiated thyroid cancer and who do not have evidence of metastatic thyroid cancer.

Potential Clinical Uses:

1. Thyrogen Tg testing may be used in patients with an undetectable Tg on thyroid hormone suppressive therapy to exclude the diagnosis of residual or recurrent thyroid cancer (see CLINICAL PHARMACOLOGY, Clinical Trials, Thyroglobulin (Tg) Results).


2. Thyrogen treatment may be used in combination with radioiodine (131I) to ablate thyroid remnants following near-total thyroidectomy in patients without evidence of metastatic disease.


3. Thyrogen testing may be used in patients requiring serum Tg testing and radioiodine imaging who are unwilling to undergo thyroid hormone withdrawal testing and whose treating physician believes that use of a less sensitive test is justified.


4. Thyrogen treatment and testing may be used in patients who are either unable to mount an adequate endogenous TSH response to thyroid hormone withdrawal or in whom withdrawal is medically contraindicated.

Considerations in the Use of Thyrogen®:

1. Even when Thyrogen-stimulated Tg testing is performed in combination with radioiodine imaging, there remains a meaningful risk of missing a diagnosis of thyroid cancer or of underestimating the extent of disease. Therefore, thyroid hormone withdrawal Tg testing with radioiodine imaging remains the standard diagnostic modality to assess the presence, location and extent of thyroid cancer.


2. Although Thyrogen appeared noninferior to thyroid hormone withholding in a study of postsurgical thyroid remnant ablation, long-term clinical outcome data are limited. Due to the relatively small clinical experience with Thyrogen in remnant ablation, it is not possible to conclude whether long-term thyroid cancer outcomes would be equivalent after use of Thyrogen or use of thyroid hormone withholding for TSH elevation prior to remnant ablation.


3. Clinicians employ a wide range of 131I activities to achieve remnant ablation in patients who have been prepared by withholding of thyroid hormone. The primary study of Thyrogen for remnant ablation employed 100 mCi ± 10% in all patients. Data are inadequate to determine if a lower dose of radioiodine would be effective when Thyrogen is used as an adjunct to radioiodine in postsurgical thyroid remnant ablation.


4. Thyrogen Tg levels are generally lower than, and do not correlate with Tg levels after thyroid hormone withdrawal (see CLINICAL PHARMACOLOGY, Thyroglobulin (Tg) Results).


5. A newly detectable Tg level or a Tg level rising over time after Thyrogen, or a high index of suspicion of metastatic disease, even in the setting of a negative or low-stage Thyrogen radioiodine scan, should prompt further evaluation such as thyroid hormone withdrawal to definitively establish the location and extent of thyroid cancer. On the other hand, none of the 31 patients studied with undetectable Thyrogen Tg levels (< 2.5 ng/mL) had metastatic disease. Therefore, an undetectable Thyrogen Tg level suggests the absence of clinically significant disease (see CLINICAL PHARMACOLOGY, Clinical Trials).


6. The decisions whether to perform a Thyrogen radioiodine scan in conjunction with a Thyrogen serum Tg test and whether and when to withdraw a patient from thyroid hormone are complex. Pertinent factors in these decisions include the sensitivity of the Tg assay used, the Thyrogen Tg level obtained, and the index of suspicion of recurrent or persistent local or metastatic disease. In the clinical trials, combination Tg and scan testing did enhance the diagnostic accuracy of Thyrogen in some cases (see CLINICAL PHARMACOLOGY, Clinical Trials).


7. The signs and symptoms of hypothyroidism which accompany thyroid hormone withdrawal are avoided with Thyrogen (see CLINICAL PHARMACOLOGY, Clinical Trials, Quality of Life, Hypothyroid Signs and Symptoms).

Precautions

(see INDICATIONS AND USAGE, Considerations in the Use of Thyrogen)

General

The use of Thyrogen (thyrotropin alfa for injection) should be directed by physicians knowledgeable in the management of patients with thyroid cancer.

There have been reports of deaths in which events leading to death occurred within 24 hours after administration of Thyrogen. A 77 year-old non-thyroidectomized patient with a history of heart disease and spinal metastases who received 4 Thyrogen injections over 6 days in a special treatment protocol experienced a fatal MI 24 hours after he received the last Thyrogen injection. The event was likely related to Thyrogen-induced hyperthyroidism. In post-marketing experience, there have been rare reports of events leading to death that occurred within 24 hours of administration of Thyrogen in patients with multiple serious medical problems. For patients for whom Thyrogen-induced hyperthyroidism could have serious consequences, hospitalization for administration of Thyrogen and post-administration observation should be considered.  Such patients might include those with known heart disease, extensive metastatic disease, or other known serious underlying illness.

Thyroglobulin (Tg) antibodies may confound the Tg assay and render Tg levels uninterpretable. Therefore, in such cases, even with a negative or low-stage Thyrogen radioiodine scan, consideration should be given to evaluating patients further with, for example, a confirmatory thyroid hormone withdrawal scan to determine the location and extent of thyroid cancer.

Thyrogen should be administered intramuscularly only. It should not be administered intravenously.

TSH antibodies have not been reported in patients treated with Thyrogen in the clinical trials, although only 27 patients received Thyrogen on more than one occasion.

Caution should be exercised when Thyrogen is administered to patients who have been previously treated with bovine TSH and, in particular, to those patients who have experienced hypersensitivity reactions to bovine TSH.

Thyrogen is known to cause a transient but significant rise in serum thyroid hormone concentration when given to patients who have substantial thyroid tissue still in situ. Therefore, caution should be exercised in patients with a known history of heart disease and with significant residual thyroid tissue (see ADVERSE REACTIONS).

It is recommended that pretreatment with glucocorticoids be considered for patients in whom local tumor expansion may compromise vital anatomic structures (such as trachea, central nervous system, or extensive macroscopic lung metastases) (see ADVERSE REACTIONS).

Careful evaluation of benefit risk relationships should be assessed for high risk elderly patients with functioning thyroid tumors undergoing Thyrogen administration. This may result in palpitations or cardiac rhythm disorder (see ADVERSE REACTIONS).

Elimination of Thyrogen is significantly slower in dialysis-dependent end stage renal disease (ESRD) patients, resulting in prolonged elevation of TSH levels (see ADVERSE REACTIONS).

Drug-Drug Interactions

Formal interaction studies between Thyrogen and other medicinal products have not been performed. In clinical trials, no interactions were observed between Thyrogen and the thyroid hormones triiodothyronine (T3) and thyroxine (T4) when administered concurrently.

The use of Thyrogen allows for radioiodine imaging while patients are euthyroid on triiodothyronine (T3) and/or thyroxine (T4). Data on radioiodine 131I kinetics indicate that the clearance of radioiodine is approximately 50% greater in euthyroid patients than in hypothyroid patients, who have decreased renal function. Thus radioiodine retention is less in euthyroid patients at the time of imaging and this factor should be considered when selecting the activity of radioiodine for use in radioiodine imaging.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term toxicity studies in animals have not been performed with Thyrogen to evaluate the carcinogenic potential of the drug. Thyrogen was not mutagenic in the bacterial reverse mutation assay. Studies have not been performed with Thyrogen to evaluate the effects on fertility.

Pregnancy Category C

Animal reproduction studies have not been conducted with Thyrogen.

It is also not known whether Thyrogen can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Thyrogen should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Thyrogen is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 16 years have not been established.

Geriatric Use

Results from controlled trials indicate no difference in the safety and efficacy of Thyrogen between adult patients less than 65 years and those greater than 65 years of age.

Adverse Reactions

Adverse reaction data were derived from post-marketing surveillance and clinical trials. The percentages in Table 4 below represent adverse reactions experienced by 481 thyroid cancer patients who participated in the clinical trials for Thyrogen. Most patients received 2 intramuscular injections, 0.9 mg of thyrotropin alfa per injection, 24 hours apart.

The safety profile of patients who received Thyrogen as adjunctive treatment for radioiodine ablation of thyroid tissue remnants who have undergone a thyroidectomy for well-differentiated thyroid cancer did not differ from that of patients who received Thyrogen for diagnostic purposes.

The most common adverse events (>5%) reported in clinical trials were nausea (11.9%) and headache (7.3%). Events reported in ≥ 1% of patients in the combined trials are summarized in Table 4. In some studies, an individual patient may have participated in both the Euthyroid Phase (Thyrogen) and Hypothyroid Phase (withdrawal).

Table 4: Summary of Adverse Events by Euthyroid Phase and Hypothyroid Phase in All Clinical Trials (≥1%)

Preferred Term	Euthyroid Phase 481 Patients n (%)	Hypothyroid Phase 418 Patients n (%)
Nausea	57 (11.9)	13 (3.1)
Headache	35 (7.3)	5 (1.2)
Fatigue	16 (3.3)	4 (1.0)
Hypercholesterolemia	0 (0.0)	13 (3.1)
Vomiting	14 (2.9)	3 (0.7)
Dizziness	12 (2.5)	0 (0.0)
Paraesthesia	8 (1.7)	0 (0.0)
Asthenia	7 (1.5)	0 (0.0)
Insomnia	7 (1.5)	0 (0.0)
Blood Cholesterol Abnormal	0 (0.0)	6 (1.4)
Diarrhea	6 (1.2)	0 (0.0)
Nasopharyngitis	5 (1.0)	0 (0.0)
Thyroglobulin Present	5 (1.0)	0 (0.0)

Post-marketing experience indicates that Thyrogen administration may cause transient (<48 hours) influenza-like symptoms [also called flu-like symptoms (FLS)], which may include fever (>100°F/38°C), chills/shivering, myalgia/arthralgia, fatigue/asthenia/malaise, headache (non-focal), and chills.

Very rare manifestations of hypersensitivity to Thyrogen have been reported in clinical trials, post-marketing settings and in a special treatment program involving patients with advanced disease: these are urticaria, rash, pruritus, flushing, and respiratory signs and symptoms.

In clinical trials no patients have developed antibodies to thyrotropin alfa, either after single or repeated (27 patients) use of the product.

Four patients out of 55 (7.3%) with CNS metastases who were followed in a special treatment protocol experienced acute hemiplegia, hemiparesis or pain one to three days after Thyrogen administration. The symptoms were attributed to local edema and/or focal hemorrhage at the site of the cerebral or spinal cord metastases. In addition, one case each of acute visual loss and of laryngeal edema with respiratory distress, requiring tracheotomy, with onset of symptoms within 24 hours after Thyrogen administration, have been reported in patients with metastases to the optic nerve and paratracheal areas, respectively. In addition, sudden, rapid and painful enlargement of locally recurring papillary carcinoma has been reported within 12-48 hours of Thyrogen administration. The enlargement was accompanied by dyspnea, stridor or dysphonia. Rapid clinical improvement occurred following glucocorticoid therapy. It is recommended that pretreatment with glucocorticoids be considered for patients in whom local tumor expansion may compromise vital anatomic structures.

There have been reports of deaths in which events leading to death occurred within 24 hours after administration of Thyrogen. A 77 year-old non-thyroidectomized patient with a history of heart disease and spinal metastases who received 4 Thyrogen injections over 6 days in a special treatment protocol experienced a fatal MI 24 hours after he received the last Thyrogen injection. The event was likely related to Thyrogen-induced hyperthyroidism. In post-marketing experience, there have been rare reports of events leading to death that occurred within 24 hours of administration of Thyrogen in patients with multiple serious medical problems. For patients for whom Thyrogen-induced hyperthyroidism could have serious consequences, hospitalization for administration of Thyrogen and post-administration observation should be considered. Such patients might include those with known heart disease, extensive metastatic disease, or other known serious underlying illness.

Information from post-marketing surveillance, as well as from the literature, suggests that elimination of Thyrogen is significantly slower in dialysis-dependent end stage renal disease (ESRD) patients, resulting in prolonged elevation of TSH levels. ESRD patients who receive Thyrogen may have markedly elevated TSH levels for several days after treatment, which may lead to increased risk of headache and nausea.

Post-marketing data include cases of atrial arrhythmias in elderly patients with pre-existing cardiac disease who received Thyrogen, and suggest that use of Thyrogen in this group should be considered carefully.

Overdosage

There has been no reported experience of overdose in humans. However, in clinical trials, three patients experienced symptoms after receiving Thyrogen doses higher than those recommended. Two patients had nausea after a 2.7 mg IM dose, and in one of these patients, the event was accompanied by weakness, dizziness and headache. Another patient experienced nausea, vomiting and hot flashes after a 3.6 mg IM dose.

In addition, one patient experienced symptoms after receiving Thyrogen intravenously. This patient received 0.3 mg Thyrogen as a single intravenous bolus and, 15 minutes later experienced severe nausea, vomiting, diaphoresis, hypotension (BP decreased from 115/66 mm Hg to 81/44 mm Hg) and tachycardia (pulse increased from 75 to 117 bpm).

Thyrogen Dosage and Administration

A two-injection regimen is recommended for Thyrogen administration.

The two-injection regimen is Thyrogen 0.9 mg intramuscularly (IM), followed by a second 0.9 mg IM injection 24 hours later.

After reconstitution with 1.2 mL Sterile Water for Injection, a 1.0 mL solution (0.9 mg thyrotropin alfa) is administered by intramuscular injection to the buttock.

For radioiodine imaging or remnant ablation, radioiodine administration should be given 24 hours following the final Thyrogen injection. Diagnostic scanning should be performed 48 hours after radioiodine administration, whereas post-therapy scanning may be delayed additional days to allow background activity to decline.

The following parameters utilized in the second Phase 3 study are recommended for diagnostic radioiodine scanning with Thyrogen:

• A diagnostic activity of 4 mCi (148 MBq) 131I should be used.


• Whole body images should be acquired for a minimum of 30 minutes and/or should contain a minimum of 140,000 counts.


• Scanning times for single (spot) images of body regions should be 10-15 minutes or less if the minimum number of counts is reached sooner (i.e. 60,000 for a large field of view camera, 35,000 counts for a small field of view).

For radioiodine ablation of thyroid tissue remnants, the activity of 131I is carefully selected at the discretion of the nuclear medicine physician. Studies with Thyrogen were conducted using 100 mCi ± 10% of 131I. Data are inadequate to determine if a lower dose of radioiodine would be effective when Thyrogen is used as an adjunct to radioiodine in postsurgical thyroid remnant ablation.

For serum Tg testing, the serum sample should be obtained 72 hours after the final injection of Thyrogen.

INSTRUCTIONS FOR USE

Thyrogen (thyrotropin alfa for injection) is for intramuscular injection to the buttock. The powder should be reconstituted immediately prior to use with 1.2 mL of Sterile Water for Injection, USP. Each vial of Thyrogen and each vial of diluent, if provided, is intended for single use. Discard unused portion of the diluent.

Thyrogen should be stored at 2-8°C (36-46°F). Each vial, after reconstitution with 1.2 mL of the accompanying Sterile Water for Injection, USP, should be inspected visually for particulate matter or discoloration before use. Any vials exhibiting particulate matter or discoloration should not be used.

If necessary, the reconstituted solution can be stored for up to 24 hours at a temperature between 2°C and 8°C, while avoiding microbial contamination.

DO NOT USE Thyrogen after the expiration date on the vial. Protect from light.

How is Thyrogen Supplied

Thyrogen (thyrotropin alfa for injection) is supplied as a sterile, non-pyrogenic, lyophilized product. It is available either in a two-vial or a four-vial kit. The two-vial kit contains two 1.1 mg vials of Thyrogen (thyrotropin alfa for injection). The four-vial kit contains two 1.1 mg vials of Thyrogen, as well as two 10 mL vials of Sterile Water for Injection, USP.

            NDC 58468-1849-4 (4-vial kit)

            NDC 58468-0030-2 (2-vial kit)

            Store at 2-8°C.

Rx ONLY

Thyrogen® (thyrotropin alfa for injection)

REFERENCES

1. Robbins RJ, Tuttle RM, Sonenberg M, Shaha A, Sharaf R, Robbins H, Fleisher M, Larson SM. Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin. Thyroid 2001; 11:865-869.


2. Robbins RJ, Larson SM, Sinha N, Shaha A, Divgi C, Pentlow KS, Ghossein R, Tuttle RM. A retrospective review of the effectiveness of recombinant human TSH as a preparation for radioiodine thyroid remnant ablation. J Nucl Med 2002; 43:1482-1488.


3. Barbaro D, Boni G, Meucci G, Simi U, Lapi P, Orsini P, Pasquini C, Piazza F, Caciagli M, Mariani G. Radioiodine treatment with 30 mCi after recombinant human thyrotropin stimulation in thyroid cancer: Effectiveness for postsurgical remnants ablation and possible role of iodine content in L-thyroxine in the outcome of ablation. J Clin Endocrinol Metab 2003; 88:4110-4115.


4. Pacini F, Molinaro E, Castagna MG, Lippi F, Ceccarelli C, Agate L, Elisei R, Pinchera A. Ablation of thyroid residues with 30 mCi 131I: A comparison in thyroid cancer patients prepared with recombinant human TSH or thyroid hormone withdrawal. J Clin Endocrinol Metab 2002; 87:4063-4068.


5. Pacini F, Ladenson P, Schlumberger M, Driedger A, Luster M, Kloos RT, Sherman S, Haugen B, Corone C, Molinaro E, Elisei R, Ceccarelli C, Pinchera A, Wahl RL, Leboulleux S, Ricard M, Yoo J, Busaidy E, Delpassand E, Hanschied H, Felbinger R, Lassmann M, Reiner C. Radioiodine Ablation of Thyroid Remnants after Preparation with Recombinant Human Thyrotropin in Differentiated Thyroid Carcinoma: Results of an International, Randomized, Controlled Study. J Clin Endocrinol Metab 2006; 91:926-932.


6. Brokhin M, Robbins R, Omry G, Martorella A, Fleisher M, Tuttle RM. Recombinant human TSH (rhTSH)-assisted radioactive iodine remnant ablation (RRA) achieves very low short term clinical recurrence rates which are not significantly different than traditional thyroid hormone withdrawal (THW). Abstract # 232, American Thyroid Assn., 2006.

Genzyme Corporation

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(800) 745-4447

Thyrogen is a registered trademark of Genzyme Corporation.

Package Label - Principal Display Panel – 4 vial Carton

NDC 58468-1849-4

Thyrogen®

thyrotropin alfa for injection

0.9 mg/mL after reconstitution

For intramuscular injection only

Carton contains 2 vials of Thyrogen® 

and 2 vials of diluent.

genzyme

Package Label - Principal Display Panel – 2 vial Carton

NDC 58468-0030-2

Thyrogen®

thyrotropin alfa for injection

0.9 mg/mL after reconstitution

For intramuscular injection only

Carton contains 2 vials of Thyrogen®

Dilute only with Sterile Water for Injection, USP.

genzyme

Thyrogen  thyrotropin alfa  injection, powder, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 58468-0030 Route of Administration INTRAMUSCULAR DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength THYROTROPIN ALFA (THYROTROPIN ALFA) THYROTROPIN ALFA 0.9 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength MANNITOL 30 mg  in 1 mL

Therahist

Generic Name: chlorpheniramine/dextromethorphan/phenylpropanolamine (klor fen IR a meen/dex troe meth OR fan/fen ill proe pa NOLE a meen)

Brand Names: Cheracol Plus, Kophane, Therahist, Threamine DM, Triaminicol Multi Symptom Cough and Cold, Tricodene Forte, Tricodene NN, Triphenicol

What is Therahist (chlorpheniramine/dextromethorphan/phenylpropanolamine)?

Chlorpheniramine is an antihistamine. It blocks the effects of the naturally occurring chemical histamine in the body. Chlorpheniramine prevents sneezing; itchy, watery eyes and nose; and other symptoms of allergies and hay fever.

Dextromethorphan is a cough suppressant. It suppresses an area in the brain that causes coughing.

Phenylpropanolamine is a decongestant. It constricts (shrinks) blood vessels (veins and arteries). This reduces the blood flow and allows nasal and respiratory (breathing) passages to open up.

Chlorpheniramine/dextromethorphan/phenylpropanolamine is used to treat nasal congestion, sinusitis (inflammation of the sinuses), and coughs associated with allergies, hay fever, and the common cold.

Phenylpropanolamine, an ingredient in this product, has been associated with an increased risk of hemorrhagic stroke (bleeding into the brain or into tissue surrounding the brain) in women. Men may also be at risk. Although the risk of hemorrhagic stroke is low, the U.S. Food and Drug Administration (FDA) recommends that consumers not use any products that contain phenylpropanolamine.

Chlorpheniramine/dextromethorphan/phenylpropanolamine may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about Therahist (chlorpheniramine/dextromethorphan/phenylpropanolamine)?

Phenylpropanolamine, an ingredient in this product, has been associated with an increased risk of hemorrhagic stroke (bleeding into the brain or into tissue surrounding the brain) in women. Men may also be at risk. Although the risk of hemorrhagic stroke is low, the U.S. Food and Drug Administration (FDA) recommends that consumers not use any products that contain phenylpropanolamine.

Use caution when driving, operating machinery, or performing other hazardous activities. Chlorpheniramine/dextromethorphan/phenylpropanolamine may cause dizziness or drowsiness. If you experience dizziness or drowsiness, avoid these activities. Use alcohol cautiously. Alcohol may increase drowsiness and dizziness while taking chlorpheniramine/dextromethorphan/phenylpropanolamine.

Do not take more of this medication than is recommended. If your symptoms do not improve, or if they worsen, talk to your doctor.

Who should not take Therahist (chlorpheniramine/dextromethorphan/phenylpropanolamine)?

Do not take chlorpheniramine/dextromethorphan/phenylpropanolamine if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects.

Before taking this medication, tell your doctor if you have

• kidney disease,


• liver disease,


• 
  

  diabetes,

  
  


• 
  

  glaucoma,

  
  


• 
  

  any type of heart disease or high blood pressure,

  
  


• 
  

  thyroid disease,

  
  


• 
  

  emphysema or chronic bronchitis, or

  
  


• 
  

  difficulty urinating or have an enlarged prostate.

  
  

You may not be able to take chlorpheniramine/dextromethorphan/phenylpropanolamine, or you may require a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.

It is not known whether chlorpheniramine/dextromethorphan/phenylpropanolamine will harm an unborn baby. Do not take this medication without first talking to your doctor if you are pregnant. This medication passes into breast milk and may harm a nursing baby. Do not take this medication without first talking to your doctor if you are breast-feeding a baby. If you are over 65 years of age, you may be more likely to experience side effects from chlorpheniramine/dextromethorphan/phenylpropanolamine. You may require a lower dose of this medication. Read the package label for directions or consult your doctor or pharmacist before treating a child with this medication. Children are more susceptible than adults to the effects of medicines and may have unusual reactions.

How should I take Therahist (chlorpheniramine/dextromethorphan/phenylpropanolamine)?

Take chlorpheniramine/dextromethorphan/phenylpropanolamine exactly as directed. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.

Take each dose with a full glass of water.

To ensure that you get a correct dose, measure the liquid form of chlorpheniramine/dextromethorphan/phenylpropanolamine with a special dose-measuring spoon or cup, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist where you can get one.

Do not take more of this medication than is recommended. An overdose of this medication can cause serious harm.

Do not take chlorpheniramine/dextromethorphan/phenylpropanolamine for longer than 7 days in a row. If your symptoms do not improve, if they get worse, or if you have a fever, talk to your doctor.

Store chlorpheniramine/dextromethorphan/phenylpropanolamine at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and take only the next regularly scheduled dose. Do not take a double dose of this medication.

What happens if I overdose?

Seek emergency medical attention.

Symptoms of a chlorpheniramine/dextromethorphan/phenylpropanolamine overdose include dry mouth, large pupils, flushing, nausea, vomiting, hyperactivity, or hallucinations.

What should I avoid while taking Therahist (chlorpheniramine/dextromethorphan/phenylpropanolamine)?

Use caution when driving, operating machinery, or performing other hazardous activities. Chlorpheniramine/dextromethorphan/phenylpropanolamine may cause dizziness or drowsiness. If you experience dizziness or drowsiness, avoid these activities. Use alcohol cautiously. Alcohol may increase drowsiness and dizziness while you are taking chlorpheniramine/dextromethorphan/phenylpropanolamine.

Therahist (chlorpheniramine/dextromethorphan/phenylpropanolamine) side effects

Serious side effects are unlikely to occur. Stop taking chlorpheniramine/dextromethorphan/phenylpropanolamine and seek emergency medical attention if you experience an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives).

Other, less serious side effects may be more likely to occur. Continue to take chlorpheniramine/dextromethorphan/phenylpropanolamine and talk to your doctor or try another similar medication if you experience

• 
  

  dryness of the eyes, nose, and mouth;

  
  


• 
  

  drowsiness or dizziness;

  
  


• 
  

  blurred vision;

  
  


• 
  

  difficulty urinating; or

  
  


• 
  

  excitation in children.

  
  

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.

What other drugs will affect Therahist (chlorpheniramine/dextromethorphan/phenylpropanolamine)?

Do not take chlorpheniramine/dextromethorphan/phenylpropanolamine if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects.

Do not take other over-the-counter cough, cold, allergy, diet, or sleep aids while taking chlorpheniramine/dextromethorphan/phenylpropanolamine without first talking to your doctor or pharmacist. Other medications may also contain chlorpheniramine, dextromethorphan, phenylpropanolamine, or other similar drugs. You may accidentally take too much of these medicines.

Chlorpheniramine/dextromethorphan/phenylpropanolamine may increase the effects of other drugs that cause drowsiness, including antidepressants, alcohol, other antihistamines, pain relievers, anxiety medicines, seizure medicines, and muscle relaxants. Dangerous sedation, dizziness, or drowsiness may occur if chlorpheniramine/dextromethorphan/phenylpropanolamine is taken with any of these medications.

Drugs other than those listed here may also interact with chlorpheniramine/dextromethorphan/phenylpropanolamine. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines.

More Therahist resources

• Therahist Drug Interactions
• Therahist Support Group
• 0 Reviews for Therahist - Add your own review/rating

Compare Therahist with other medications

• Cold Symptoms

Where can I get more information?

• Your pharmacist has additional information about chlorpheniramine/dextromethorphan/phenylpropanolamine written for health professionals that you may read.

What does my medication look like?

Many formulations of chlorpheniramine/dextromethorphan/phenylpropanolamine are available over-the-counter. Ask your pharmacist any questions you have about this medication, especially if it is new to you.

Triplex AD

Generic Name: chlorpheniramine, pyrilamine, and phenylephrine (KLOR fe NEER a meen, pir IL a meen, FEN il EFF rin)

Brand Names: AllerTan, Chlorex-A 12, Conal, MyHist-PD, Nalex A 12, Phena-Plus, Phena-S, Poly Hist PD, R-Tannate, Ru-Hist Forte, Tri-Hist Pediatric, Triotann-S Pediatric, Triple Tannate Pediatric, Triplex AD

What is chlorpheniramine, phenylephrine, and pyrilamine?

Chlorpheniramine and pyrilamine are antihistamines that reduce the effects of natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose.

Phenylephrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).

The combination of chlorpheniramine, phenylephrine, and pyrilamine is used to treat runny or stuffy nose, sneezing, itching, watery eyes, and sinus congestion caused by allergies, the common cold, or the flu.

Chlorpheniramine, phenylephrine, and pyrilamine may also be used for purposes not listed in this medication guide.

What is the most important information I should know about chlorpheniramine, phenylephrine, and pyrilamine?

Do not use this medicine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects. Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Ask a doctor or pharmacist before using any other cold, cough, allergy, or pain medicine. Antihistamines and decongestants are contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains an antihistamine or decongestant. This medication may cause blurred vision and may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly. Drinking alcohol can increase drowsiness caused by chlorpheniramine, phenylephrine, and pyrilamine. Before using chlorpheniramine, phenylephrine, and pyrilamine, tell your doctor if you regularly use other medicines that make you sleepy (such as sedatives, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression, or anxiety). They can add to sleepiness caused by chlorpheniramine and pyrilamine.

What should I discuss with my healthcare provider before taking chlorpheniramine, phenylephrine, and pyrilamine?

Do not use this medicine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects. You should not use this medication if you are allergic to chlorpheniramine, phenylephrine, pyrilamine, or to other decongestants, or if you have:

• 
  

  severe or uncontrolled high blood pressure;

  
  


• 
  

  severe coronary artery disease;

  
  


• 
  

  diabetes;

  
  


• 
  

  overactive thyroid; or

  
  


• 
  

  asthma, pneumonia, or other breathing problems.

  
  

Ask a doctor or pharmacist if it is safe for you to take this medicine if you have:

• liver disease;


• kidney disease;


• 
  

  heart disease or high blood pressure;

  
  


• 
  

  glaucoma;

  
  


• 
  

  enlarged prostate;

  
  


• 
  

  bladder obstruction or other urination problems; or

  
  


• 
  

  a blockage in your digestive tract (stomach or intestines).

  
  

FDA pregnancy category C. It is not known whether chlorpheniramine, phenylephrine, and pyrilamine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. Chlorpheniramine, phenylephrine, and pyrilamine can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are using chlorpheniramine, phenylephrine, and pyrilamine.

How should I take chlorpheniramine, phenylephrine, and pyrilamine?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Cough or cold medicine is usually taken only for a short time until your symptoms clear up.

Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Do not crush, chew, or break an extended-release tablet. Swallow the pill whole. Breaking or crushing the pill may cause too much of the drug to be released at one time.

Measure liquid medicine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

Shake the oral suspension (liquid) well just before you measure a dose. Store at room temperature away from moisture, heat, and light.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include dry mouth, dilated pupils, nausea, vomiting, and warmth, redness, or tingly feeling under your skin.

What should I avoid while taking chlorpheniramine, phenylephrine, and pyrilamine?

Ask a doctor or pharmacist before using any other cold, cough, allergy, or pain medicine. Antihistamines and decongestants are contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains an antihistamine or decongestant. This medication may cause blurred vision and may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly. Drinking alcohol can increase certain side effects of this medication.

Avoid taking this medication if you also take diet pills, caffeine pills, or other stimulants (such as ADHD medications). Taking a stimulant together with a decongestant can increase your risk of unpleasant side effects.

Chlorpheniramine, phenylephrine, and pyrilamine side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have a serious side effect such as:

• 
  

  severe dizziness, anxiety, restless feeling, or nervousness;

  
  


• 
  

  fast, pounding, or uneven heartbeats;

  
  


• 
  

  confusion, hallucinations, unusual thoughts or behavior;

  
  


• 
  

  feeling like you might pass out;

  
  


• 
  

  urinating less than usual or not at all;

  
  


• 
  

  easy bruising or bleeding, unusual weakness, fever, chills, body aches, flu symptoms;

  
  


• 
  

  increased blood pressure (severe headache, blurred vision, trouble concentrating, chest pain, numbness, seizure); or

  
  


• 
  

  nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

  
  

Less serious side effects may include:

• 
  

  upset stomach, constipation;

  
  


• 
  

  dry mouth;

  
  


• 
  

  blurred vision;

  
  


• 
  

  dizziness, drowsiness;

  
  


• 
  

  problems with memory;

  
  


• 
  

  sleep problems (insomnia); or

  
  


• 
  

  feeling restless or excited (especially in children).

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect chlorpheniramine, phenylephrine, and pyrilamine?

Cold or allergy medicine, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression or anxiety can add to sleepiness caused by chlorpheniramine or pyrilamine. Tell your doctor if you regularly use any of these medicines, or any other cough and cold medications.

Tell your doctor about all other medications you use, especially:

• 
  

  digoxin (Lanoxin);

  
  


• 
  

  blood pressure medication;

  
  


• 
  

  an antidepressant;

  
  


• 
  

  a barbiturate such as phenobarbital (Solfoton) and others;

  
  


• 
  

  a diuretic (water pill);

  
  


• 
  

  medication to treat irritable bowel syndrome;

  
  


• 
  

  bladder or urinary medications such as oxybutynin (Ditropan, Oxytrol) or tolterodine (Detrol);

  
  


• 
  

  aspirin or salicylates (such as Disalcid, Doan's Pills, Dolobid, Salflex, Tricosal, and others); or

  
  


• 
  

  a beta-blocker such as atenolol (Tenormin), carteolol (Cartrol), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), timolol (Blocadren), and others.

  
  

This list is not complete and there may be other drugs that can interact with chlorpheniramine, phenylephrine, and pyrilamine. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Triplex AD resources

• Triplex AD Side Effects (in more detail)
• Triplex AD Use in Pregnancy & Breastfeeding
• Triplex AD Drug Interactions
• Triplex AD Support Group
• 0 Reviews for Triplex AD - Add your own review/rating

• Chlorpheniramine/Phenylephrine/Pyrilamine MedFacts Consumer Leaflet (Wolters Kluwer)


• AllerTan Suspension MedFacts Consumer Leaflet (Wolters Kluwer)


• Phena-S Liquid MedFacts Consumer Leaflet (Wolters Kluwer)


• Poly Hist PD Prescribing Information (FDA)


• Ru-Hist Forte Controlled-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Triplex AD with other medications

• Cold Symptoms
• Hay Fever

Where can I get more information?

• Your pharmacist can provide more information about chlorpheniramine, phenylephrine, and pyrilamine.

See also: Triplex AD side effects (in more detail)

Triple sulfa vaginal

Generic Name: triple sulfa vaginal (TRIH pull SUL fa)

Brand Names: Gyne Sulf, Sultrin Triple Sulfa, Trysul, V.V.S.

What is triple sulfa vaginal?

Triple sulfa is an antibacterial medication. It fights bacteria in the body.

Triple sulfa vaginal is used to treat vaginal infections caused by the bacteria Gardnerella vaginalis.

Triple sulfa vaginal may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about triple sulfa vaginal?

Use this medication for the full amount of time prescribed by your doctor or recommended in the package even if you begin to feel better. Your symptoms may improve before the infection is completely healed.

Avoid wearing tight-fitting, synthetic clothing (such as pantyhose) that does not allow air circulation. Wear loose-fitting clothing made of cotton and other natural fibers until the infection is healed.

Avoid getting this medication in the eyes, nose, or mouth.

What should I discuss with my healthcare provider before using triple sulfa vaginal?

Do not use triple sulfa vaginal if you have ever had an allergic reaction to it or to another sulfa-based medicine.

Triple sulfa vaginal is in the FDA pregnancy category C. This means that it is not known whether triple sulfa vaginal will be harmful to an unborn baby. Do not use this medication without first talking to your doctor if you are pregnant. Triple sulfa passes into breast milk and may affect a nursing baby. Do not use this medication without first talking to your doctor if you are breast-feeding a baby.

How should I use triple sulfa vaginal?

Use triple sulfa vaginal exactly as directed by your doctor or follow the directions that accompany the package. If you do not understand these instructions, ask your pharmacist, nurse, or doctor to explain them to you.

Wash your hands before and after using this medication.

Insert the tablet or cream into the vagina using the applicator as directed. Triple sulfa vaginal is usually used twice a day, in the morning and evening.

Use this medication continuously for the prescribed amount of time, even during your menstrual period.

A sanitary napkin can be worn to prevent the medication from staining clothing but do not use a tampon.

If the infection does not clear up after one course of therapy has been finished, or if it appears to get worse, see your doctor. You may have another type of infection.

Avoid getting this medication in the eyes, nose, or mouth. Store triple sulfa vaginal at room temperature away from moisture and heat.

What happens if I miss a dose?

Apply the missed dose as soon as you remember. However, if it is almost time for the next dose, skip the dose you missed and apply only the next regularly scheduled dose. Do not use a double dose.

What happens if I overdose?

An overdose of triple sulfa vaginal is unlikely to occur. If you do suspect that a much larger than normal dose has been used or that triple sulfa vaginal has been ingested, contact an emergency room or a poison control center.

What should I avoid while using triple sulfa vaginal?

Avoid wearing tight-fitting, synthetic clothing (e.g., panty hose) that does not allow air circulation. Wear loose-fitting clothing made of cotton and other natural fibers until the infection is healed.

Avoid sexual intercourse or use a condom to prevent spreading the infection to a sexual partner.

Triple sulfa vaginal side effects

Stop using triple sulfa vaginal and seek emergency medical attention if you experience an allergic reaction (shortness of breath; closing of the throat; swelling of the lips, face, or tongue; or hives).

Other, less serious side effects may be more likely to occur. These include burning, itching, irritation of the skin, and an increased need to urinate.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.

What other drugs will affect triple sulfa vaginal?

Avoid using other vaginal creams or douches during treatment with triple sulfa, unless otherwise directed by your doctor.

Drugs other than those listed here may also interact with triple sulfa vaginal. Talk to your doctor and pharmacist before taking any prescription or over the counter medicines, including herbal products.

More triple sulfa vaginal resources

• Triple sulfa vaginal Support Group
• 0 Reviews for Triple sulfa - Add your own review/rating

Compare triple sulfa vaginal with other medications

• Bacterial Vaginitis

Where can I get more information?

• Your pharmacist has additional information about triple sulfa vaginal written for health professionals that you may read.

What does my medication look like?

Triple sulfa vaginal is available with a prescription under several brand names. Other brand or generic formulations may also be available. Ask your pharmacist any questions you have about this medication, especially if it is new to you.

• 
  

  Sultrin Triple Sulfa vaginal tablets

  
  


• 
  

  Sultrin Triple Sulfa vaginal cream

  
  


• 
  

  Dayto Sulfa vaginal cream

  
  


• 
  

  Gyne-Sulf vaginal cream

  
  


• 
  

  Trysul vaginal cream

  
  


• 
  

  V.V.S. vaginal cream